Cholesterol Lowering Drugs & Antioxidants as Therapeutic Strategy in Patients with High Cholesterol

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Cholesterol Lowering Drugs & Antioxidants as Therapeutic Strategy in Patients with High Cholesterol

Abstract: Oxidized LDL has been acquiring notable importance as arteriosclerosis genesis, a fact which determines the therapeutic strategy to control such cholesterol fraction. The authors included 20 patients with high cholesterol levels, measuring the lipid peroxidation (MDA) and modification on the fundamental substance (90% defined as Free Radicals -- FR), divided in 3 groups: A) using cholesterol lowering drugs, B) using the association of cholesterol lowering drugs and antioxidants, C) using exclusively antioxidants. They concluded that the association of cholesterol lowering drugs and antioxidants decreases circulating levels of cholesterol, increases the HDL fraction, and diminishes the lipid peroxidation, measurement used to indirectly establish the LDL oxidation.

The great majority of papers deal with cholesterol, lowering it to acceptable serum levels, increasing HDL, and diminishing the LDL fraction as a control factor for atherogenesis secondary to high levels of serum cholesterol.( 1-3)

The oxidized low density lipoproteins contribute to atherosclerosis and that's one of the reasons why oxidized LDL is considered a risk factor for cardiovascular disease.( 4)

Oxidized LDL is recognized by specific macrophage's surface receptors, uptake and converted into foam cells, accumulating in the vascular endothelium causing greasy lesions.( 5, 6)

The lipids are transported through the plasma by lipoproteins which contain different types of lipids (triglycerides, cholesterol, cholesterol esters and phospholipids) and protein (apolipo protein).( 7)

The chylomicrons (rich in triglycerides) contain various apolipoproteins that activate the lipoprotein lipase, being removed by various cells receptors.

LDL is the cascade final product, containing particularly apo-B. LDL lipoproteins interact with LDL receptors on the membranes of liver cells and other peripheral cells like smooth muscle and fibroblasts. They are definitely atherogenic when they cross blood vessel walls.( 8, 9)

The protein component of lipoproteins is called apolipoprotein: Apo A-1 is the main protein of HDL, as apo B to LDL.

The apolipoproteins are very important for transporting and metabolism of the lipoproteins; by the following mechanisms:

a) lipoproteins are transport vehicles, although the apo directs lipid tissue distribution.

b) apos determine if lipids are stored in tissues (like artery walls) or metabolized in the liver.

c) apos can regulate the place where atherosclerotic lesions can occur.( 10, 11)

It is important also to identify the lipoprotein a (Lp) which is lipid bound to Apo B. These two molecules are bound to apo-a which is different from Apo A found on HDL.

Apo a bonds to endothelial cells (like plasminogen) and fibrin, clot builder. Such phenomenon damages vessel walls resulting in the formation of clots containing fibrin which attracts apo a. The apo a bonds to lipoprotein a and to the clot, storing in the endothelium developing the ateromatous plaque.( 12)

Apo A represents approximately 60% of HDL proteins, and is the responsible agent for the activation of cholesterol acyltransferase lecithin which catalyzes the esterification of cholesterol.

Apo B determine 90% of the LDL mass, and participate in the recognition of cell receptors for the LDL catabolism.

Some recent considerations define the risk for atherosclerosis classification based on the cholesterol fractions:

High LDL & low Lp a = low risk.

Low LDL & high Lp a = moderate risk

High LDL & high Lp a = high risk( 13)

Material And Methods

20 patients were included, 10 male and 10 female, divided in 3 groups, A) 5 patients using only cholesterol lowering drugs; B) 10 patients using the association of cholesterol lowering drugs and antioxidants; C) 5 patients using only antioxidants.

All patients in the study had coronary disease history. Among the total, 11 patients (55%) had had previous myocardial infarction.

The laboratory evaluation was performed considering that the patient have not taken any medication which could directly alter the cholesterol metabolism in the last 30 days. The exams taken after fasting and reevaluated 90 days later were: total cholesterol, HDL levels, malonyldialdehyde (MDA) levels( 14) to measure lipid peroxidation via tribarbituric acid, cell analysis in vivo by optical microscopy defining the measurement of the quality and amount of free radicals (FR) by the modifications of the fundamental substance.( 15, 16)

The cholesterol lowering drug used was Simvastatin which has inhibitor effect on the hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) on single daily doses of 10 mg.( 17)

The antioxidant contained: Vitamin E -- 60 IU to inhibit the lipid peroxidation; Vitamin C -- 120 mg to recuperate oxidized Vitamin E and to inhibit hydroxyl radicals, as to favor the recuperation of collagen; Vitamin B2 (riboflavin) -- 3.4 mg acts like intermediate in the formation of the enzyme glutathione peroxidase for the inhibition of the lipid peroxidation; Beta carotene -- 10,000 IU (approximately 15 mg) in the control of superoxides, hydroxyl radicals, and singlet oxygen; Vitamin B6 in the form of pyridoxal-5-phosphate -- 4 mg inhibiting the formation of homocystine (chemical atherogenic agent on the arterial endothelium); reduced glutathione -- 50 mg, act in the formation of glutathione peroxidase; Selenium, as Selenium methionine -- 100 mcg to potentialize Vitamin E, and in the formation of glutathione peroxidase, both inhibiting lipid peroxidation, and Tulin -- 80 mg which acts favoring the phagocyte activity of macrophages (element considered dispensable in the formula).( 18-20)

Results: The results are shown in Table 1, presenting values obtained from patients among the treatment groups. A detailed analysis is very important for better comprehension of the significant statistics achieved, since its importance would show motives that induce the use of an antioxidant strategy for the preventive treatment of high levels of cholesterol.

In Table 2 we observe that after 90 days of Simvastatin administration both group A (exclusively Simvastatin) and group B (Simvastatin + Antioxidants - SA) showed a 12% decrease in total cholesterol levels, although group C (exclusively Antioxidants - A) showed an unexplainable reduction of total cholesterol -- 1%. From this table we conclude that Simvastatin is an important cholesterol lowering drug, an effect not achieved with the antioxidant formula used for this study.

In Table 3, we show a similar analysis with HDL levels, and the most important characteristic observed, is that in group S the HDL increase less than half compared with the group using the association SA (Group B), and in the group that used exclusively antioxidants (A), the HDL increase was unexplained, although with this similar analysis we conclude that the association of cholesterol lowering drugs and antioxidants has a synergetic effect over the increase of HDL in patients under treatment for cholesterol control.

Table 4 shows the measurement of free radicals (FR) by modification of the fundamental matrix of the extracellular system, measured by optical microscopy. Interesting that a slight increase of FR levels is observed in group A, although group B and C have a significant decrease in the FR level, more expressive however nonimportant statistically in the group that used the association SA.

Theoretically it would be suggested that the cause of FR increase in the group using exclusively cholesterol lowering drugs is the consequence of the inhibition of the coenzyme Q10 by Simvastatin, as described by some researchers.( 21)

Finally in Table 5, we observe the MDA of group A had a lowering of MDA levels unexplainable if compared with the lowered lipid peroxidation obtained on the groups using exclusively antioxidants or the association with cholesterol lowering drugs.

We would like to emphasize that all 20 patients concluded the study and there were no problems with lowering the doses or patients quitting the study because of effects, showing a great tolerance for the pharmaceutical products tested.

Discussion: Cholesterol has been considered the most important external risk factor for atherogenesis, and for some time the therapeutic strategies were aimed at decreasing the total cholesterol and LDL and the increasing of HDL. Although the importance of oxidation of LDL is reason for study, it is a necessity to establish the antioxidant priorities in such circumstances.

The cholesterol liberated by lysosomes hydrolyses inhibits the enzyme HMG-CoA reductase, increasing the formation of acid coenzyme A tranferase, which synthesizes the intercellular esterified cholesterol. The intracellular cholesterol inhibits the LDL membrane receptors, blocking its entrance, controlling the storage of the cholesterol inside tissues by the feedback mechanism.( 22, 23)

When LDL is oxidized, a lack of ability to get into the arterial endothelium occurs on regular cells, only the "scavenger" receptors (macrophages) are able to go through the endothelium by the foam cells effect that induce atherogenesis. Oxidized LDL also stimulates the chemical taxia factor of monocytes (MCPI) and the growth factor of macrophages (MCSF), although these two are inhibited by high density lipoproteins, that protect the endothelium from contact with LDL, those when penetrating, begin the transformation process of the atheroma.( 24, 25)

With the results achieved, our study clearly shows that the lipid peroxidation process is closely related to cholesterol metabolism, and the indirect measurements of lipid peroxidation can offer data about the oxidative potential of LDL as an atherogenic factor in high risk populations prone to developing cardiovascular disease.

It is certain that the therapeutic success in atherosclerosis control and its risk factors can be involved with a relevant participation of Free Radicals and cholesterol oxidation, although other studies have considered the Free Radicals participation in some other risk factors as follows:

a) high blood pressure, by nitric oxide oxidation (endothelial relaxing factor), with vessel contraction effect over the endothelium against its biochemical constitution.( 26)

b) obesity, substratum of lipid peroxidation.( 27)

c) smoking, enormous number of FR on each cigarette, besides containing a series of heavy metals that act as intermediates of the oxidation processes, and by its vasoconstriction effect -- nicotine dependent.( 28, 29)

d) sedentarism, that favors obesity.( 30)

e) stress, by the constant liberation of adrenergic transmitters favoring the production of hydrogen peroxide as the result of the final metabolism noradrenaline.( 31, 32)

The results achieved clearly show that Simvastatin is an important cholesterol lowering drug, although with no effect on lipid peroxidation. The antioxidants inhibit lipid peroxidation, as well as the estimation of the total FR, with no effect over total cholesterol although the synergism between Simvastatin and the Antioxidants is the one with the best effect, lowering the cholesterol, the lipid peroxidation, the FR total number, and more interesting, the better response of increasing HDL.

Our study with its small number of patients, represents only a beginning showing the necessity for better studies for cholesterol and its fractions, as well as pondering the possibility of including an antioxidant strategy in the oxidized cholesterol control, inhibiting its atherogenic activity.( 32,33)

The conclusions are evident, although far from being definitive, since more studies are necessary to define the scope of the antioxidant activity controlling cholesterol oxidation. This study complements others showing that the use of antioxidants is being imposed with greater frequency on different factors that can accelerate atherosclerosis and its consequences on the cardiovascular system.

Simvastatin shows itself effective in lowering cholesterol, with poor or nonantioxidant activity. The formula with vitamins, minerals and nutrients showed as a potent antioxidant, with practically no cholesterol lowering activity, although their simultaneous use demonstrated an important antioxidant effect and cholesterol lowering, beyond the greater increase in HDL levels achieved with the synergism.

It is extremely important to include antioxidants associated with cholesterol lowering drugs in the strategy of cholesterol control and atherogenesis inhibition with the goal of inhibiting the oxidation of the LDL cholesterol fraction.

References
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(3.) SSSG. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease. Lancet, 1994;344:1383-9.

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(11.) Maciejko J. et al. Apo A-1 as a marker of angiographically assessed coronary artery disease. NEJM. 1983;309:385-89.

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(13.) Rath M. Eradication of Heart Disease. 1992.

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(15.) Olszewer E. Microscopia Optica como metodo de medida de RL. Tecnopress. 1995.

(16.) Olszewer E. Coronary diseases, antioxidants and FR. Measurements during stress test. TLfDP 1994.

(17.) NEJM. Vol 32,pp 1491-1498, 1995.

(18.) Howard N. et al Serial coronary angiographic evidence that antioxidant Vitamin intake reduces progression of coronary artery atherosclerosis. JAMA 1995;273: 1849-1854. Simon et al, Vitamin C and heart disease. The Nut. Rep. Aug. 1992;10(8):57-64.

(19.) Jailal et al. Inhibition of LDL oxidation by beta carotene. Circulation Supp II, Oct 1991;84(4):II-449/Abst 1789.

(20.) Jacques Paul. Relationship of Vitamin C status and cholesterol and blood pressure. New York Ac. of Sci. February 1992, 9-12.

(21.) Coghan, Andy. Vitamin E could reduce heart disease. New Scientist. May 25,1991;24.

(22.) Sniderman A. et al. Association of coronary atherosclerosis with hiperapobetalipoproteinemia. Proc. NY Ac. of Sci. 1980;77:604-8.

(23.) Snideman et al. Apo b and A-1 as predictors of coronary artery disease. Can. J. Card. 1988;4(SA):24A-30A.

(24.) Steinberg D. et al. Beyond Cholesterol. Modifications of LDL that increase its atherogenecity. NEJM 1989;320:915-24.25.

(25.) Kyu Taik Lee Ed. Nutrition in Cardiocerebrovascular disease. Annals of the NY Ac. Sci. Vol 676 1993.

(26.) Chang Chiueh Ed. The Neurobiology of NO. Annals of the NY Ac. Sci. Vol. 738, 1994.

(27.) Whitney and Rolfes. Understanding Nutrition. 7th Ed. West. Publ. Co. 1995.

(28.) Olszewer E. Manual de Medicina Ortomolecular Ed. N.L. Editorial. 1995.

(29.) Oliveira J de M. A teoria Ottomolecular em Medicina Clinica. Artezen 2000,1995.

(30.) Halpern et al. Risco cardiovascular, fatores metabolicos e nutricionais. Dx e tratamento. Asta Med. Ltda. 1994.

(31.) Olszewer E. Radicais Livres em Medicina. 2da Ed. 1996. Byk Ed.

(32.) Olszewer E. Stress. Revista Racine N 1, 1996.

Townsend Letter for Doctors & Patients.

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By B. Wagon; M. Gilberd and E. Olszewer

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